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Novel Approaches to Targeting TSC1/TSC2 Across Malignancies
Volume 1
Issue 1

Nab-sirolimus Under Investigation in TSC1- and TSC2-mutated Gynecologic Cancers and Other Solid Tumors


Kathleen N. Moore, MD, MS, discusses the incidence of TSC1 and TSC2 mutations in different gynecologic tumor types, the trial design and eligibility criteria for the PRECISION 1 study, and the importance of genetic testing to identify these mutations and treat them early.

Kathleen N. Moore, MD, MS

Kathleen N. Moore, MD, MS

The mTOR inhibitor nab-sirolimus (ABI-009) may emerge as an effective and tolerable treatment in patients with gynecologic cancers with TSC1 and TSC2 mutations, according to Kathleen N. Moore, MD, MS.

The phase 2 PRECISION 1 trial (NCT05103358) is investigating nab-sirolimus in patients with solid tumors with pathogenic alterations in the TSC1 or TSC2 genes.1 This trial is currently enrolling.

Nab-sirolimus was previously studied in patients with advanced perivascular epithelioid cell neoplasms (PEComas) in the phase 2 AMPECT trial (NCT02494570), which led to the FDA approval of this agent in PEComas on November 22, 2021.2

“Nab-sirolimus is albumin-bound sirolimus, which is an mTOR inhibitor,” Moore said. “We’re using it in situations where mTOR inhibitors are felt to be effective, because it’s felt to be a more effective mTOR inhibitor.”

In an interview with OncLive®, Moore discussed the incidence of TSC1 and TSC2 mutations in different gynecologic tumor types, the trial design and eligibility criteria for the PRECISION 1 study, and the importance of genetic testing to identify these mutations and treat them early.

Moore is the associate director of Clinical Research at the Stephenson Cancer Center, as well as the director of the Oklahoma TSET Phase I Program and a professor in the Section of Gynecologic Oncology at The University of Oklahoma College of Medicine in Oklahoma City.

OncLive®: How prevalent are TSC1 and TSC2 mutations in gynecologic cancers?

Moore: TSC1 and TSC2 are proteins within the PI3K/AKT/mTOR pathway, which is why we’re interested in them when we’re talking about mTOR inhibitors and nab-sirolimus. TSC1 and TSC2 are a convergence point downstream of PI3K/AKT, as well as downstream from RAS, RAF, MEK, and ERK. They’re a convergence point ahead of mTORC1. [These mutations are] a potential marker of loss of TSC1 or TSC2, novel development targets that are key upstream regulators of mTOR activity.

TSC1 and TSC2 are uncommon across all solid tumors. The most common tumor types for TSC1 and TSC2 combined include bladder [cancer, which] is the biggest solid tumor site with loss of TSC1 or TSC2, most commonly TSC1. Bladder is followed by hepatobiliary cancer, of which almost 5% has TSC1 or TSC2 loss, with TSC2 being more commonly lost.

Then, in endometrial cancer, about 3.3% have these losses, and it’s more of an even split. About 2% of those losses are of TSC1, and a little over 1% are of TSC2. Almost 3% of ovarian cancer has this loss, about half a percent less than endometrial cancer, and [those losses are] predominantly TSC1 at 1.85% vs [TSC2 at] 0.92%. [A bit of this loss is seen in] cervical cancer, and almost all of it is TSC2, a little less than 1%.

Soft tissue sarcoma is a broad term for many different sarcomas. In general, almost 3% of soft tissue sarcomas have TSC1 and TSC2 loss; about 1.3% is TSC1 loss, and 1.7% is TSC2 loss. Leiomyosarcomas are considered soft tissue sarcomas, so for our patients who have, for example, uterine leiomyosarcoma, TSC1 and TSC2 would be targets I’d look for in those patients, especially given that the initial indication for nab-sirolimus is in PEComas, which are rare sarcomas. I would want to keep an eye out for TSC1 or TCSC2 mutations in soft tissue sarcoma cases, as well.

What unmet needs currently exist for patients with TSC1 or TSC2 mutations, especially as this is a small population?

We don’t know yet. We assume these mutations probably fall within The Cancer Genome Atlas subgroup that’s copy number low, microsatellite stable, where there are possibly estrogen receptors, progesterone receptors, and beta catenin, but we don’t know if they’re all microsatellite stable or if none of them have ERBB2 mutations, for example. In general, for patients who have advanced or recurrent endometrial cancer, once they have seen chemotherapy and immunotherapy in whatever form those are given, we don’t have a lineup of effective therapies for anyone, although we’re trying hard to develop them.

We have good therapies for frontline metastatic endometrial cancer. Immunotherapy probably plays a role there or in the second line with or without lenvatinib [Lenvima]. After that, there isn’t effective therapy.

A novel therapy capitalizing on the loss of TSC1 and TSC2 would fit there, at least in that third-line setting. However, we don’t know if it’s better than some of these other therapies at this point. A high unmet need exists post standard of care [SOC], which is not a long runway right now for uterine cancer.

What is known so far about the mTOR inhibitor nab-sirolimus, and how could it potentially benefit patients who have TSC1 or TSC2 loss?

mTOR inhibitors aren’t new. They have been around for a long time. mTOR signaling pathways coordinate cell growth and metabolism through many environmental cues that include growth factors and nutrients. Dysregulated mTOR signaling, which is common in many solid tumors and probably in hematologic tumors, as well, implicates the initiation and progression of cancers.

While we’ve been trying to target this pathway, we focused way up the pathway at [targets like] PI3K inhibitors, which haven’t been very effective for gynecologic cancers as of yet, although we’re still studying them.

[Our attention then] turned to downstream effectors with these mTOR inhibitors. There are many of these, mainly TORC1 inhibitors, and there are new generation mTOR inhibitors that hit TORC1 and TORC2. These have been around for a while, and they are relatively modestly effective agents, that are National Comprehensive Cancer Network–listed for treatment of endometrial cancer.

We can use temsirolimus and sometimes everolimus. These are nice additions to our armamentarium, but the response rates aren’t particularly high, and there’s not been a selection for them yet.

This particular agent, nab-sirolimus, is [both simple and complex]. Sirolimus is a known mTOR inhibitor, and it has many uses. It’s an mTOR immunosuppressant. It’s interestingly used post organ transplantation in cardiology and oncology. It has an oral formulation. It’s poorly water soluble and has many CYP348 interactions.

The nab technology is a method of binding therapies to albumin, in this case, sirolimus. That makes it possible to give [this drug intravenously (IV), without the need for] cremophor EL or other solvents because it’s now soluble. By being bound to albumin, sirolimus achieved better tumor targeting and better uptake in preclinical models. We know this from other nab agents like nab-paclitaxel [Abraxane], which is another albumin-bound taxane. This isn’t new, it’s just new with this combination.

The thought was that [using nab-sirolimus] would translate into better efficacy by increasing the amount of drug we’d get into tumors and hopefully safety, as well. Much preclinical work suggests this is true. The nab-sirolimus IV dosing was compared with oral dosing sirolimus or everolimus. These different studies demonstrated much higher drug accumulation in the tumor and [showed that the agent] appears to inhibit tumor growth in a superior fashion to the oral counterparts. [Investigators reported] a higher area under the curve using nab-sirolimus than with any of the other non-albumin bound mTOR inhibitors, as well as a higher Cmax, which hopefully translates to increased efficacy. [These trials] led to phase 1 studies, and then eventually, the study that led to the first FDA approval for nab-sirolimus in advanced or malignant PEComa.

The PRECISION 1 basket trial is going to investigate nab-sirolimus in solid tumors with TSC1 or TSC2 mutations. What is the rationale and design of this study?

This basket trial came out of findings from the AMPECT trial, which was the phase 2 registrational trial of nab-sirolimus in PEComa. In that particular study, patients needed to have advanced PEComa that was inoperable. They could not have had a prior mTOR inhibitor.

These patients received nab-sirolimus at 100 mg/m2 on day 1 and day 8 every 21 days and were followed until progression or toxicity. Nab-sirolimus had a 39% response rate, which is high for PEComa, where almost nothing works. This was felt to be a landmark achievement for these rare tumors. This was a 31-patient study that led to FDA approval [of the agent in] this rare tumor without good options, a true orphan disease.

[In addition to the good response rate,] the duration of response [DOR] was long. The patients hadn’t hit the median DOR at the 2-year follow-up point. Nab-sirolimus [elicited] prolonged responses and disease stabilization, even among patients who didn’t have a response.

[Although these are small numbers, the investigators did see] TSC1 and TSC2 mutations in the PEComas. They noticed that the patients most likely to [have lengthy responses] to nab-sirolimus were those with TSC2 mutations, for the most part, and then TSC1 mutations, to a lesser extent.

Of the patients who had neither, there was maybe 1 who responded, and those patients didn’t benefit as much or as long from nab-sirolimus. That brought up the possibility of TSC1 and TSC2 as predictive biomarkers in other solid tumors for use of nab-sirolimus.

From the AMPECT study, of the patients who had TSC1 and TSC2 mutations combined, 14 patients of the whole 31-patient study, the response rate for TSC2 was 89%. For TSC1, it was 20% among the 5 patients with TSC1 mutations. [These were] small numbers, but there did appear to be a signal here.

That study led to the development of PRECISION 1, which is a basket study, TSC-007, evaluating nab-sirolimus in a variety of tumors with TSC1 and TSC2 pathologic inactivating mutations. [It doesn’t include] all TSC1 and TSC2 mutations; they have to be pathogenic inactivating mutations.

These are rare, but we do find them. We next-generation sequence [NGS] many tumors now, and when [these mutations are] recurring, we will find them. If you search portals, you’ll find patients right now who have TSC1 or TSC2 mutations.

[The study is a large basket study and will enroll] 120 patients who are naïve to mTOR inhibitors and have a good ECOG performance status. They must have a solid tumor with TSC1 or TSC2 pathogenic inactivating alterations by NGS; it can’t be determined by liquid biopsy. [Patients must have also] exhausted appropriate SOC options.

They will receive nab-sirolimus at the same dosage as in the PEComa study, 100 mg/m2 on days 1 and 8 every 21 days. It’s a 30-minute infusion, so it’s not long. [The trial is] divided 60/60, so 60 patients will have TSC1 mutations, and 60 will have TSC2 mutations. Patients will be followed for overall response rate and DOR and treated until disease progression or toxicity. The trial is open and enrolling now, just launching nationwide, and is starting to look for patients who may benefit.

How might findings from this trial benefit patients with gynecologic cancers with these specific mutations?

We’re going to have to see. There are some data from an expanded access program with nab-sirolimus [that happened] before this trial launch. It’s limited data, with 8 patients who had ovarian cancer, endometrial cancer, or sarcoma. They were heavily pretreated, at a median of 3 prior lines. Of the 7 patients who were evaluable for response, 5 had a partial response. These were small numbers, but it seemed that TSC1 or TSC2 mutations predicted a group of patients who would respond to therapy.

[Nab-sirolimus was also] well tolerated. Treatment-emergent adverse effects included those we see with mTOR inhibitors, including edema. Mucositis is a key toxicity, so patients should still use prophylactic dexamethasone mouthwash. Nail changes and some gastrointestinal [GI] toxicity with vomiting [have also been reported]. You can see some hypertension with this as well. The majority of these, though, were grades 1 and 2.

These are early numbers, but this is what we’re trying to do. This is an individualized selection of therapy where we identify what appears to be a driver mutation for this particular tumor, and we use an effective agent that has a high expectation of response and at least based on the PEComa data, good durability. However, we need to see, as we expand and get appreciable numbers in other solid tumors: Are the responses as good or hopefully better? Are they of a long duration?

This could be a game changer for patients who have TSC1 or TSC2 mutations if we show that nab-sirolimus is highly active and durable. It appears to be a well-tolerated agent and doesn’t cause the hair loss and bone marrow toxicity of standard chemotherapy. I could see moving this up in lines of therapy, so that [patients could have] what appears to be a tolerable and effective therapy much earlier with a differentiated safety profile from other standard interventions.

[This is an] opportunity to target therapy where it belongs, and then figure out when [to use it]. How early in lines of therapy do we use this? These types of studies would not have been possible until NGS became widely available and cost effective, so we could identify these rare mutations in a broad swath of patients and make sure that they know about [their mutations] and have access to these agents.

How important is genetic testing when individualizing treatments in gynecologic cancers?

It’s incredibly important. We send NGS routinely now in many of our tumors, once they are advanced and we expect that we’re going to be treating with multiple lines of therapy. For recurrent or early-stage disease, we’re not often sending NGS if it’s not going to affect our therapy at that point.

Most patients now in oncology are getting appropriate NGS, and [TSC1 and TSC2 mutations are] on all the panels, so we should be picking up [these mutations] appropriately as we’re testing patients and looking for other charts, targetable mutations, or findings.

For example, microsatellite instability in endometrial cancer or homologous recombination deficiency in ovarian cancer, are largely done on NGS assays. [Those tests will] give you that information in addition to other results, and you may pick up TSC1 or TSC2 mutations.

[Those mutations] needs to be recognized as potentially actionable now. In the past, we might have looked at that [assay and decided against mTOR inhibitors, thinking they weren’t] incredibly active. We might have gone to another treatment and ignored TSC1 and TSC2 as potential biomarkers. Now, however, this open-label trial moves treatment with this novel formulation of an mTOR inhibitor up in interest for patients who have this mutation.

In much of drug development around these rare molecular alterations or mutations, we have [an interesting] model for opening studies. Maybe I won’t find any TSC1 or TSC2 mutations in the next year, it’s possible, or I might see 5, who knows? [Opening this trial and potentially not enrolling patients to it is] risky for many institutions, [which is why] this and other studies are trying to employ just-in-time mechanisms more broadly.

[These mechanisms] are hard to do in academic settings but can be easier outside of academic settings. A site can go through some of the startup and be primed and ready to be activated, but they’re never activated until they have a patient. That way, they’re not having to keep up all the regulatory efforts that still cost money and take time, unless they have a patient to go on the trial.

Those just-in-time mechanisms have been around for a while, but were not widely used, because they were still clunky. We’re figuring it out now. Studies like PRECISION 1 will benefit from that, and more importantly, patients will benefit.

If a patient is in a part of the country that doesn’t have a big academic center with this trial open, but they’re found to have a TSC1 or TSC2 mutation, then hopefully the study can be activated nearer to them in relatively short order so they can participate. This should ideally increase equity and access to trials. That’s the hope, but we’ll see as the efforts roll out with this. There are examples [of how this type of trial] translates to improved access to trials in other tumors, so I’m optimistic that it will [improve access in this case].

What main message would you like to leave with colleagues regarding nab-sirolimus and its investigation within gynecologic cancers in PRECISION 1?

I hope my colleagues who take care of people with gynecologic malignancies will be excited about this. It is daunting because I live in a big academic bubble where my whole job is thinking about mutations and clinical trials and trying to match patients to the best therapies. I’m not in the operating room 4 days a week, but my busy Humana Oncology partners are, [and this is] yet another rare mutation they need to watch out for. Do they open the trial? Do they not open the trial? These are difficult decisions for my hardworking colleagues, and I recognize that.

My message to them is to think about how we can develop tools that would be useful to our smart gynecologic oncologists and medical oncologists who are dealing with other [drugs, treatments, and mutations] that they need to remember and keep track of for all these tumors. [We should] develop tools and matching algorithms that help keep these potentially targetable mutations front-of-mind either within electronic medical records or with communications so we can do some of the work for them.

Relying on busy clinicians to remember [a mutation that occurs in] 1% of patients is hard, it’s a big ask. I hope they’re excited about this. I hope they see this as a potential big add-on for a small subset of our patients. I hope that in this and other rare molecular subtypes or gynecologic cancers, they will help us brainstorm how to best do testing, triage how and when patients can access these agents and trials outside the ivory towers to improve equity and access, and help our providers maintain their sanity trying to keep all this straight. The world is becoming more complex, and we need to do a better job of providing tools that help our colleagues keep track of all these new discoveries.


  1. Phase 2 basket trial of nab-sirolimus in patients with malignant solid tumors with pathogenic alterations in TSC1 or TSC2 genes (PRECISION 1). Updated October 12, 2022. Accessed October 20, 2022.
  2. FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. News release. FDA. November 23, 2021. Accessed October 20, 2022.
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